1. Field of the Invention
This invention relates to a novel neurotransmitter Neuropeptide Y receptor, its nucleic acid sequence, and compounds, compositions, and methods for their use.
2. Summary of the Related Art
Neuropeptide Y (NPY) is a 36-amino acid peptide neurotransmitter that is located throughout the central and peripheral nervous systems. Tatemoto, Proc. Natl. Acad. Sci. USA 79, 5485 (1982); Hazlewood, Proc. Soc. Exp. Biol. Med. 202, 44 (1993). It affects a broad range of phenomena, including blood pressure regulation, memory, anxiolysis/sedation, food and water appetite, vascular and other smooth muscle activity, intestinal electrolyte secretion, and urinary sodium excretion. E.g., Colmers and Wahlestedt, The Biology of Neuropeptide Y and Related Peptides (Humana Press, Totowa, N.J. 1993); Kalra et al., Phys. & Behavior 50, 5 (1991).
Peptide YY (PYY) is also a 36 amino acid peptide and has significant sequence homology (70%) to NPY. Tatemoto et al., Nature 296, 659 (1982). Its anatomical distribution is similar to that of NPY, although it is located mainly in the endocrine cells of the lower gastrointestinal tract. Bottcher et al., Regul. Pept. 8, 261 (1984). Like NPY, PYY stimulates feeding in rats. Morley et al., Brain Res. 341, 200 (1985). Along with the pancreatic polypeptide (PP), NPY and PYY have a common tertiary structure, characterized by the so-called PP-fold. Glover, Eur. J. Biochem. 142, 379 (1985). Both NPY and PYY show about a 50% sequence homology with PP.
Because of their structural similarities, NPY and PYY have a number of common receptors. At least four receptor subtypes, Y1, Y2, Y3, and Y4/PP, have been identified. The affinity for NPY, PYY, and various fragments thereof varies among the subtypes. See, e.g., Bard et al (WO 95/17906) and references cited therein. For example, Y1 and Y2 subtypes have high affinity for NPY and PYY. Whereas Y1 has a high affinity for (Leu.sup.31 Pro.sup.34)NPY (LP)NPY) and low affinity for (13-36)NPY, Y2behaves oppositely. Y3has high affinity for NPY but low affinity for PYY. Y4/PP has a high affinity for PP but relatively low affinity for NPY.
Wahlestedt (WO 93/24515) and Larhammar et al., (J. Biol. Chem. 267, 10935) (1992)) describe the cloning and identification of the human Y1-type NPY/PYY receptor isolated from human fetal brain tissue. Selbie et al. (WO 93/09227) disclosed the full length cDNA sequence of the Y1 receptor from human hippocampus. Eva et al. (FEBS Lett. 271, 81 (1990)) cloned the NPY Y1 receptor from rat forebrain. Eva et al. (FEBS Lett. 314, 285 (1992)) cloned the NPY Y1 receptor from murine genomic DNA.
The Y2-type receptor has also been cloned. Gerald et al. (WO 95/21245) disclosed the cDNA sequence of human hippocampal Y2 and two rat Y2 clones. Rose et al. (J. Biol. Chem. 270, 22661 (1995)) disclosed the cDNA sequence of the Y2 receptor from a human neuroblastoma cell line.
Bard et al., (supra) and Lundell et al. (J. Biol. Chem. 270, 29123 (1995)) described cloning the cDNA sequence of the Y4/PP receptor from both rat spleen and human placenta.
To date, the Y3 receptor has not been cloned.
Because of the important role of NPY and PYY in a number of physiological processes, such as feeding, there is a strong need to further develop materials and methods for investigating the mechanistic behavior of these compounds and for treating diseased and other abnormal states associated with the physiological processes in which NPY and PYY act. Specifically, the NPY analogs/fragments that induce feeding, such as (LP)(3-36)NPY, do not bind to the previously identified NPY/PYY receptors with affinities consistent with the feeding response. Accordingly, there is a need and desire to identify the NPY/PYY receptor that is responsible for the feeding response. Antagonists to such a receptor could be used to treat obesity and diabetes by reducing appetite and food consumption.